Indirect evidence of selective glial involvement in glutamate-based mechanisms of mood regulation in depression: Meta-analysis of absolute prefrontal neuro-metabolic concentrations

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Abstract

Proton magnetic resonance spectroscopy (1H MRS) measures glutamatergic metabolites namely glutamate and glutamine located in neurons and astrocytes respectively. In this meta-analysis the contribution of glutamatergic neurotransmission to depressive symptoms was evaluated together with other putative prefrontal metabolites described in the pathogenesis of mood disorders, and in relation to treatment effects. A comprehensive literature search up to 2014 identified 17 reports which measured absolute concentrations of neurometabolites in the prefrontal cortex with 1H MRS meeting criteria for inclusion in this meta-analysis. Excess of heterogeneity was investigated with meta-regressions. The analyses showed an exclusive reduction in absolute values of the composite measure of Glutamine and Glutamate (Glx) in the prefrontal cortex in depression, correlating in meta-regression analyses with treatment severity. Glutamate measurements in isolation did not differ vs. healthy controls or in relation to treatment and/or clinical improvement. Similarly there were no significant changes in other neurometabolites at baseline and following treatment. The analysis supports a role for glutamatergic dysfunction in the pathogeneses of mood dysregulation. The reduction in the absolute Glx values in the absence of changes in glutamate levels, suggests a possible modulatory role of astrocytes in the pathophysiology of depression.

Introduction

The glutamate hypothesis of depression represents a novel addition to monoaminergic hypotheses of mood disregulation. Magnetic resonance spectroscopy (1H MRS) measures glutamatergic metabolites namely glutamate and glutamine located in neurons and astrocytes respectively. Previous work using absolute and relative metabolite concentrations indicated prefrontal glutamatergic neurotransmission downregulation in depression (Luykx et al., 2012, Taylor, 2014). In this meta-analysis, the contribution of glutamatergic neurotransmission to depressive symptoms was appraised 1) by evaluating absolute concentrations of glutamatergic metabolites to minimize the interference of internal reference signals in the interpretation of findings, 2) in relation to other putative prefrontal metabolites described in the pathogenesis of mood disorders, and 3) following a course of treatment. We hypothesized that a reduction in absolute values of Glutamine and Glutamate (composite measure, Glx) would support glutamatergic downregulation in depression. Glx measurements are believed to represent the combined signal of glutamine and glutamate with minor contributions from glutathione and GABA (Maddock and Buonocore, 2012). Current models suggest that up to 80% of glutamate is compartmentalized in neurons whilst glutamine is mainly stored in astrocytes (Maddock and Buonocore, 2012, Waagepetersen et al., 2007). Hence we predicted that in the absence of a decrease in Glutamate levels, a reduction in Glx might suggest primarily an aberrant metabolic glutamatergic pathway of glial origin (Ongur et al., 2008; Chitty et al., 2013).

Section snippets

Search strategy and inclusion/exclusion criteria

A range of electronic databases was systematically searched including web of knowledge, EMBASE, EBSCO PsycARTICLES, OVID, and PubMED, further complemented by manual searches and bibliographic cross-referencing. Keywords used independently and in combination to identify the studies included: depression, bipolar disorder, magnetic resonance spectroscopy or MRS, biomarker, glutamine, glutamate, glutamix, NAA, choline, GABA, GAMMA, and Myo-Inositol. Studies were included if they 1) presented

Literature search

Seventeen reports were suitable for inclusion in the meta-analysis (Figure 1 and Table 1). All the studies compared participants with unipolar depression and healthy controls apart from one study which included one participant with bipolar depression (Auer et al., 2000). Voxel placement in the prefrontal cortex varied across the studies (Table 1). Sixteen studies were cross-sectional (Auer et al., 2000, Ajilore et al., 2007, Gruber et al., 2003, Frey et al., 2003, Michael et al., 2003,

Discussion

This work evaluated summary effect sizes of absolute concentrations of prefrontal metabolites in major depression investigated by using proton magnetic resonance spectroscopy. To our knowledge this is the first meta-analysis globally measuring prefrontal absolute metabolic concentrations at baseline and in relation to treatment effects. In keeping with previous work showing glutamatergic hypofunction in depression (Luykx et al., 2012, Yüksel and Öngür, 2010, Taylor, 2014) the data reviewed

Role of the funding source

This study presents independent research part-funded by the National Institute for Health Research (NIHR) Biomedical Research Center at South London and Maudsley NHS Foundation Trust and King׳s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. DA research is supported by the Academy of Medical Sciences (AMS-SGCL8).

Contributors

ANM was involved in literature searches and data extraction. DA was involved in the analyses and in writing the first draft of the report. SJ, BC and JC provided supervision, statistical expertise, and offered guidance in the interpretation of the results. JC had a role in overall supervision and final drafting of the report. All the authors contributed to and have approved the final manuscript.

Conflict of interest

Nothing to declare

Acknowledgment

DA would like to thank colleagues who supplemented their published work with detailed auxiliary information: Dr Simone Grimm, Dr Hanna Järnum Lilholt, Dr Elna-Marie Larsson. ANM would like to thank Dr Mortimer and Theresa Sackler Foundation for their support. DA would also like to thank Mariana Wieske for her help with figure preparation and editing.

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